Ciclesonide for the treatment of airway disease in horses

ABSTRACT

The invention relates to the field of medicine, in particular to the field of veterinary medicine. The invention relates to glucocorticoids, especially ciclesonide or a pharmaceutically acceptable derivative thereof, for the treatment of airway disease in horses, such as pulmonary disease, preferably recurrent airway obstruction (RAO), Summer Pasture Associated Obstructive Pulmonary disease (SPAOPD), and inflammatory airway disease (IAD).

FIELD OF THE INVENTION

The invention relates to the field of medicine, in particular to thefield of veterinary medicine. The invention relates to glucocorticoidsor inhaled glucocorticoids, especially ciclesonide or a pharmaceuticallyacceptable derivative thereof, for the treatment of airway disease inhorses, such as pulmonary disease, preferably recurrent airwayobstruction (RAO), summer pasture associated obstructive pulmonarydisease (SPAOPD), and inflammatory airway disease (IAD).

BACKGROUND INFORMATION

Equine airway disease is a prominent disease in many horses. It can bedivided into the diseases of the upper and lower airways. There are anumber of equine lower airway diseases with noninfectious origin such asRAO (or heaves or equine chronic obstructive pulmonary disease), IAD,SPAOPD and exercise induced pulmonary hemorrhage (EIPH). The latter istypically diagnosed in racehorses. RAO, IAD and SPAOPD are discs easeswith an allergic background. Rarely diagnosed additional lower airwaydisorders are granulomatous, neoplastic and interstitial pneumonias. Theinfectious diseases of the lower airway include bronchitis, pneumonia,pleuritis or a combination of these caused by viral, bacterial, fungaland parasitic agents (Kutasi et al., 2011).

Common phenotypic manifestations of airway disease in horses includecoughing, nasal discharge, increased respiratory effort and poorperformance or exercise intolerance. Additionally, fever, depression,decreased appetite and weight loss can be observed in infectious airwaydiseases (Couetil et al., 2007 and Kutasi et al., 2011).

Equine airway diseases with an allergic background cannot be cured butonly kept asymptomatic. The known therapies for these horses includechanges in the environment and the administration of different drugs.The aim of the change in the stable environment is to improve airwayquality and to reduce the allergen exposure of the horses, which mighttrigger the exacerbations of RAO, SPAOPD and IAD. The following drugsare used for the treatment of airway diseases with noninfectious origin:glucocorticoids, bronchodilators (β2 agonists and anticholinergicagents), and mucosolvants (dembrexin and acetylcystein). In addition,antibiotics are administered for infectious airway diseases. Prominentside effects of these standard therapies are tachycardia, mydriasis, andcolic for bronchodilators and adrenocortical suppression (reduction inthe blood serum levels of cortisol), laminitis, hepatopathy, musclewasting, altered bone metabolism, increased susceptibility to infection(neutrophilia, lymphopenia) and decreased antibody response tovaccination for glucocorticoids (Couetil et al., 2007, Dauvillir et al.,2011).

The problem underlying the present invention is to provide a medicationfor horses which allows the treatment of airway disease in horses whilereducing the risk of side effects for the treated animals.

BRIEF SUMMARY OF THE INVENTION

It has been surprisingly found that ciclesonide or a pharmaceuticallyacceptable salt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof is particularly advantageousfor the use in a method of treating an airway discs ease in equines,preferably horses. An advantage of the present invention is the absenceor reduction of side effects. The administration of glucocorticoids candecrease the production of cortisol by thehypothalamic-pituitary-adrenal (HPA) axis. Thus, measurement of serumcortisol level is generally used as surrogate marker of glucocorticoidsystemic activity and a tool for assessing systemic bioavailability ofglucocorticoids. Such a reduction of equine serum cortisol levels occursin state of the art treatment options including drug administration viaa peroral or parenteral (e.g. dexamethasone, prednisone) as well as viaan inhalative (beclomethasone, fluticasone proprionate and budesonide)route. In contrast, no decrease in the serum cortisol level of horses isobserved after treatment for two weeks with different dose levels ofciclesonide (see Examples 2-3).

In addition, the treatment option provided by the present inventionminimizes the risks associated with complications caused by alteredmetabolism or compromised immune system, etc. (see backgroundinformation). Neutrophilia and lymphopenia is commonly observed afterthe state of the art treatment with dexamethasone (see example 4, Table2). This can lead to increased susceptibility to infections. Incontrast, no alteration is observed in the immune system of horsesmeasured by neutrophilia and lymphopenia after treatment for two weekswith different dose levels of ciclesonide (see example 4, Table 2).

Another advantage of the present invention is treatment convenience. Thestate of the art treatment with dexamethasone does not allow theadministration of constantly high dose levels for a longer time perioddue to the risk of developing side effects. Therefore, the dose ofdexamethasone has to be continuously adjusted after treatment initiationconsidering a number of factors (e.g. route of drug administration,medical history, clinical condition and body weight of the horse) withthe aim to prevent or minimize side effects while administering a highenough dose for assuring clinical efficacy. In contrast, the presentinvention provides a superior treatment option for horses with a lowerrisk for developing side effects. Thus, it does allow for a treatmentover long periods of time at constantly high dose levels with assuringthe required clinical efficacy, which is comparable to dexamethasone.

Furthermore, the safety profile of ciclesonide is also more advantageouscompared to other aerosol glucocorticoids like fluticasone. There areconflicting reports about the effect of fluticasone on cortisol levels.In some studies fluticasone shows significant suppression in measuredcortisol levels in both humans and horses after aerosol administration(Robinson et al., 2009 and Grahnén et al., 1997). In contrast, there isno or clinically not relevant cortisol suppression with ciclesonide inhumans or in horses after aerosol inhalation.

An additional advantage of the present invention is the prodrug natureof ciclesonide. It has been shown that the active metabolite,C21-C21-desisobutyrylciclesonide, is generated in the airways of humansor other mammals. The prodrug ciclesonide has to be activated by specialenzymes in the airway tissues in order to generateC21-21-desisobutyrylciclesonide, which is the effective molecule. Theexistence of such special enzymes in the equine airway tissues has notbeen previously reported. Other substances like fluticasone, which isnot a prodrug, do not need enzymatic conversion to be able to be activein the lungs of horses or other mammals. The present inventionsurprisingly demonstrates for the first time that ciclesonide can beconverted into the effective molecule C21-C21-desisobutyrylciclesonidein horses (please see example 5) and that ciclesonide administrationthus results in a beneficial therapeutic effect in horses with airwaydisease.

Furthermore, ciclesonide undergoes reversible fatty acid esterificationswith fatty acids in human lung tissue. The fatty acid conjugates mayserve as a depot. It has not been previously reported whether the sameesterification process occurs in equine lung tissues as well or not.Other substances like fluticasone do not generate fatty acid conjugatesin human lung tissues at all.

Therefore, even if large amounts of ciclesonide are swallowed duringaerosol treatment the prodrug nature of ciclesonide, the dependency ofC21-C21-desisobutyrylciclesonide generation on specific enzymeconversion and a quick liver metabolism ofC21-C21-desisobutyrylciclesonide assures that the effect of ciclesonideis only related to the airways and not to the whole body of the horses.This is also referred to as topic effect of ciclesonide. In contrast,the state of the art treatment with dexamethasone or other substanceslike fluticasone leads to a systemic exposure of the active metabolite,leading to an extensive side effect profile (see backgroundinformation).

The present invention concerns ciclesonide or a pharmaceuticallyacceptable salt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof for use as a medicament fortreating an equine, preferably a horse. The present invention concernsciclesonide or a pharmaceutically acceptable salt thereof or acomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof for use in a method of treating an equine, preferably a horse.

The present invention concerns ciclesonide or a pharmaceuticallyacceptable salt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof for the use in a method oftreating an airway disease in equines, preferably horses. The presentinvention concerns ciclesonide or a pharmaceutically acceptable saltthereof or a composition comprising ciclesonide or a pharmaceuticallyacceptable salt thereof for the use in a method of treating (an) airwaydisease(s) in (an) equine(s), preferably in (a) horse(s).

According to a specific aspect of the present invention said ciclesonideor said pharmaceutically acceptable salt thereof or said compositioncomprising ciclesonide or said pharmaceutically acceptable salt thereofis inhalable/(in the form of) an inhalant. In another aspect of thepresent invention the ciclesonide or the pharmaceutically acceptablesalt thereof or the composition comprising ciclesonide or thepharmaceutically acceptable salt thereof is in a liquid formulation,preferably an ethanolic formulation, which can be aerosolized tofacilitate its inhalation. In a further aspect of the present inventionthe liquid formulation is partially ethanolic and partially aqueous. Ina further aspect of the present invention the liquid formulationcomprises one or more of the solvents: water, ethanol,hydrofluoroalkane(s) such as HFA 227 and HFA 134a, hydrofluoroolefin(s)such as HFO-1234ze, and optionally additional excipients. HFA is anabbreviation for hydrofluoroalkane and HFO is an abbreviation forhydrofluoroolefin.

In a preferred aspect of the present invention the solvent of the liquidformulation comprises/consists of a mixture of ≥85% V/V ethanol and ≤15%V/V water, such as for example 10% V/V aqueous and 90% V/V ethanol. Inanother preferred aspect of the present invention the solvent of theliquid formulation comprises a mixture of ethanol and water, whereby theproportion of ethanol is in the range of 85-100% V/V, preferably 90-95%V/V. Preferably the proportion of ethanol is 90% V/V ethanol. In aspecific aspect of the present invention the formulation (inhalationsolution) of ciclesonide is as follows:

Ingredient Content Ciclesonide 0.7-3.1 g/100 mL Hydrochloric acid ad[H⁺] = 10^(−3.5) to 10⁻⁵ mol/L 90% V/V ethanol/water ad 100 mLwhere the concentration of hydrogen ions [H⁺] can be measured, forexample, by potentiometric titration.

A further aspect of the present invention is the application of theliquid formulation using an inhalation device, such as the RESPIMAT®inhaler or another inhalation device using the RESPIMAT®aerosol-generating technology. The RESPIMAT® inhaler is disclosed forexample in WO 97/12687, which is hereby incorporated by reference. Thisinhaler can advantageously be used to produce the inhalableaerosols/inhalants according to the invention. The dose of activesubstance delivered ex RESPIMAT® inhaler can be calculated from:

-   -   the concentration of active substance in the liquid formulation        (inhalation solution) [μg/μ],    -   the “delivered volume”, defined as the volume of liquid expelled        from the RESPIMAT® inhaler per actuation [μL]. The delivered        volume ex RESPIMAT® inhaler has been found to be approximately        11 μL per actuation,        according to the following formula:        Dose[μg]=Concentration[μg/μL]·Delivered Volume[μL]

The invention further concerns ciclesonide or a pharmaceuticallyacceptable salt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof for the use (in a method) forthe management/treatment of airway disease in equines, preferablyhorses. Preferably the airway disease is a pulmonary disease. Theinvention further concerns ciclesonide or a pharmaceutically acceptablesalt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof for the use (in a method) forthe management/treatment of recurrent airway obstruction (RAO) inequines, preferably horses. The invention further concerns ciclesonideor a pharmaceutically acceptable salt thereof or a compositioncomprising ciclesonide or a pharmaceutically acceptable salt thereof forthe use (in a method) for the management/treatment of summer pastureassociated obstructive pulmonary disease (SPAOPD) in equines, preferablyhorses. The invention further concerns ciclesonide or a pharmaceuticallyacceptable salt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof for the use (in a method) forthe management/treatment of inflammatory airway disease (IAD) inequines, preferably horses.

The invention further concerns a method of treating an airway diseasecomprising administering a therapeutic effective amount of ciclesonideor a pharmaceutically acceptable salt thereof or a compositioncomprising ciclesonide or a pharmaceutically acceptable salt thereof toan equine patient, preferably a horse, in need thereof. Preferably theairway disease is a pulmonary disease. In a specific aspect of saidmethod of treatment of the present invention ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof isadministered as an inhalable/inhalant. In a further specific aspect ofthe method of treatment of the present invention ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof is in a liquidformulation, preferably with a solvent comprising/consisting of ethanol,water or a combination thereof. In another aspect of the method oftreatment of the present invention ciclesonide or a pharmaceuticallyacceptable salt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof is administered via an (equine)inhalation device. In a preferred aspect of the method of treatment ofthe present invention ciclesonide or a pharmaceutically acceptable saltthereof or a composition comprising ciclesonide or a pharmaceuticallyacceptable salt thereof is in a liquid formulation with a solventcomprising/consisting of a mixture of ethanol and water which isadministered via an (equine) inhalation device.

In a specific aspect of the present invention (ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof for the use ina method for treating an airways disease and/or a method of treatmentwith ciclesonide or a pharmaceutically acceptable salt thereof or acomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof) the airway disease is a pulmonary disease. In another aspect ofthe present invention the airway disease is selected from the groupconsisting of: recurrent airway obstruction (RAO), summer pastureassociated obstructive pulmonary disease (SPAOPD), and inflammatoryairway disease (IAD). In a preferred aspect of the present invention theairway disease is recurrent airway obstruction (RAO).

In another specific aspect of the present invention ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof isadministered via an (equine) inhaler device. Preferably said inhalerdevice comprises: (a) a pressurized metered dose inhaler or anaqueous/ethanolic droplet inhaler such as the RESPIMAT® inhaler oranother inhalation device using the RESPIMAT® aerosol-generatingtechnology and (b) an adapter for equine use. In yet another specificaspect of the present invention ciclesonide or said pharmaceuticallyacceptable salt thereof or said composition comprising ciclesonide orsaid pharmaceutically acceptable salt thereof is a partially ethanolicformulation and is administered via an (equine) inhaler device.

In a further aspect of the present invention (ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof for the use ina method for treating an airways disease and/or a method of treatmentwith ciclesonide or a pharmaceutically acceptable salt thereof or acomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof) said ciclesonide or said pharmaceutically acceptable saltthereof or said composition comprising ciclesonide or saidpharmaceutically acceptable salt thereof is administered at a dose of atleast 900 μg ex inhaler, at least 1800 μg ex inhaler, or at least 2700μg ex inhaler, preferably at least 2400 μg ex inhaler or at least 2700μg ex inhaler. In yet another aspect of the present invention saidciclesonide or said pharmaceutically acceptable salt thereof or saidcomposition comprising ciclesonide or said pharmaceutically acceptablesalt thereof is administered at a dose of 100 μg to 5000 μg ex inhaler,450 μg to 2700 μg ex inhaler, 900 μg to 2400 μg ex inhaler, 900 μg to2700 μg ex inhaler, preferably at a dose of 900 μg to 2700 μg exinhaler. In another specific aspect of the present invention those dosesare administered twice daily for 5-7 days followed by once daily for 5-7days. Preferably, ciclesonide or said pharmaceutically acceptable saltthereof or said composition comprising ciclesonide or saidpharmaceutically acceptable salt thereof is administered at a dose of2700 μg twice daily for 5-7 days followed by a dose of 3712.5 μg oncedaily for 5-7 days. According to a preferred aspect of the presentinvention ex inhaler is ex RESPIMAT® inhaler.

In another aspect of the present invention (ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof for the use ina method for treating an airways disease and/or a method of treatmentwith ciclesonide or a pharmaceutically acceptable salt thereof or acomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof) said ciclesonide or said pharmaceutically acceptable saltthereof or said composition comprising ciclesonide or saidpharmaceutically acceptable salt this administered with 20 or feweractuations per dose, preferably 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1actuations, most preferably it is administered using 8 or feweractuations per dose.

In a specific aspect of the present invention the composition comprisingciclesonide or a pharmaceutically acceptable salt thereof is preparedfor administration at a concentration of 0.7-3.1 g ciclesonide/100 mL or1.0-3.1 g ciclesonide/100 mL inhalation solution. Preferably it isprepared for the administration with 20 or fewer actuations per dose,preferably 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 actuations per dose,most preferably the composition is prepared for the administration using8 or fewer actuations per dose.

In a specific aspect of the present invention (ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof for the use ina method for treating an airways disease and/or a method of treatmentwith ciclesonide or a pharmaceutically acceptable salt thereof or acomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof) said ciclesonide or said pharmaceutically acceptable saltthereof or said composition comprising ciclesonide or saidpharmaceutically acceptable salt thereof is administered in 1 to 3 dosesper day, preferably 1 or 2 doses are administered per day/once daily. Inanother specific aspect of the present invention said ciclesonide orsaid pharmaceutically acceptable salt thereof or said compositioncomprising ciclesonide or said pharmaceutically acceptable salt thereofis administered once daily. In a further specific aspect of the presentinvention said ciclesonide or said pharmaceutically acceptable saltthereof or said composition comprising ciclesonide or saidpharmaceutically acceptable salt thereof is administered in 1 to 4 dosesper week (e.g. every 2. day, that is 3.5 doses per week).

In a specific aspect of the present invention the composition comprisingciclesonide or a pharmaceutically acceptable salt thereof ismade/prepared with/for the administration of a concentration of 0.7-3.1g ciclesonide/100 mL or 1.0-3.1 g ciclesonide/100 mL. Preferably it isprepared for the administration in 1 to 3 doses per day, preferably 1 or2 doses per day. Preferably it is prepared for the administration of 1to 2 doses once daily. In a further specific aspect of the presentinvention the composition comprising ciclesonide or a pharmaceuticallyacceptable salt thereof is prepared for the administration in 1 to 3doses per week.

In yet another aspect of the present invention (ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof for the use ina method for treating an airways disease and/or a method of treatmentwith ciclesonide or a pharmaceutically acceptable salt thereof or acomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof), said ciclesonide or said pharmaceutically acceptable saltthereof or said composition comprising ciclesonide or saidpharmaceutically acceptable salt thereof is administered over anextended time period of at least 1 week, at least 2, 3, 4, 5, 6, 7, 8,9, or 10 weeks or more. In a preferred aspect of the present inventionsaid ciclesonide or said pharmaceutically acceptable salt thereof orsaid composition comprising ciclesonide or said pharmaceuticallyacceptable salt thereof is administered in 1-2 doses daily over anextended time period. In a specific aspect said time period is at least1 week, which can be extended to at least 2, 3, 4, 5, 6, 7, 8, 9, or 10weeks or more. Preferably said ciclesonide or said pharmaceuticallyacceptable salt thereof or said composition comprising ciclesonide orsaid pharmaceutically acceptable salt thereof is administered in 1 or 2doses daily over an extended period, whereby said period is preferablyat least 1 week, which can be extended to at least 2, 3, 4, 5, 6, 7, 8,9, or 10 weeks or more.

In a specific aspect of the present invention the composition comprisingciclesonide or a pharmaceutically acceptable salt thereof is preparedfor the administration at a concentration of 0.7-3.1 g ciclesonide/100mL or 1.0-3.1 g ciclesonide/100 mL inhalation solution. Preferably thecomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof is prepared for the administration over an extended time periodof at least 1 week, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks ormore. In a preferred aspect of the present invention the compositioncomprising ciclesonide or a pharmaceutically acceptable salt thereof isprepared for the administration in 1 or 2 doses daily over an extendedtime period of at least 1 week, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10weeks or more, most preferably the composition comprising ciclesonide ora pharmaceutically acceptable salt thereof is prepared for theadministration in 1 dose daily over an extended period of at least 1week, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks or more.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Budesonide study: Temporal variations in transpulmonary presssure (ΔP_(L)) associated with the administration of dexamethasone (blackbars) and three different doses of budesonide applied with the RESPIMAT®inhaler (450 μg (nozzle A): white bars, 900 μg (nozzle A): striped, 1800μg (nozzle A): crossed) between days 0 and 14 (mean±SEM) (n=8), whereSEM is “Standard Error of the Mean”.

FIG. 2: Budesonide study: Temporal variations in breathing effort scoreassociated with the administration of dexamethasone (black bars) andthree different doses of budesonide applied with the RESPIMAT® inhaler(450 μg (nozzle A): white bars, 900 μg (nozzle A): striped, 1800 μg(nozzle A): crossed) between days 0 and 14 (mean±SEM) (n=8)

FIG. 3: Budesonide study: Temporal variations in serum cortisolassociated with the administration of dexamethasone (black bars) andthree different doses of budesonide applied with the RESPIMAT® inhaler(450 μg (nozzle A): white bars, 900 μg (nozzle A): striped 1800 μg(nozzle A): crossed) between days 0 and 14 (mean±SEM) (n=8)

FIG. 4: Ciclesonide 1^(st) study: Temporal variations in transpulmonarypressure (ΔP_(L)) associated with the administration of dexamethasone(black bars) and three different doses of ciclesonide applied with theRESPIMAT® inhaler (450 μg (nozzle A): white bars, 900 μg (nozzle A):striped, 1800 μg (nozzle A): crossed) between days 0 and 14 (mean±SEM)(n=8)

FIG. 5: Ciclesonide 1^(st) study: Temporal variations in serum cortisolassociated with the administration of dexamethasone (black bars) andthree different doses of ciclesonide applied with the RESPIMAT® inhaler(450 μg (nozzle A): white bars, 900 μg (nozzle A): striped, 1800 μg(nozzle A): crossed) between days 0 and 14 (mean±SEM) (n=8)

FIG. 6: Ciclesonide 2^(nd) study: A) Temporal variations intranspulmonary pressure (ΔP_(L)) associated with the administration ofdexamethasone (black bars) and three different doses of ciclesonideapplied with the RESPIMAT® inhaler (1687.5 μg (nozzle B): white bars,2700 μg (nozzle A): striped, 2700 μg (nozzle B): crossed) between days 0and 14 (mean±SEM) (n=8)

B) Temporal variations in lung resistance (R_(L)) associated with theadministration of dexamethasone (black bars) and three different dosesof ciclesonide applied with the RESPIMAT® inhaler (1687.5 μg (nozzle B):white bars, 2700 μg (nozzle A): striped, 2700 μg (nozzle B): crossed)between days 0 and 14 (mean±SEM) (n=8)

FIG. 7: Ciclesonide 2^(nd) study: Temporal variations in weightedclinical score associated with the administration of dexamethasone(black bars) and three different doses of ciclesonide applied with theRESPIMAT® inhaler (1687.5 μg (nozzle B): white bars, 2700 μg (nozzle A):striped, 2700 μg (nozzle B): crossed) between days 0 and 14 (mean±SEM)(n=8)

FIG. 8: Ciclesonide 2^(nd) study: Temporal variations in serum cortisolassociated with the administration of dexamethasone (black bars) andthree different doses of ciclesonide applied with the RESPIMAT® inhaler(1687.5 μg (nozzle B): white bars, 2700 μg (nozzle A): striped, 2700 μg(nozzle B): crossed) between days 0 and 14 (mean±SEM) (n=8)

FIG. 9: Ciclesonide 3^(rd) study: A) Temporal variations intranspulmonary pressure (ΔP_(L)) associated with the administration ofplacebo (white bars) and three different dose schedules of ciclesonideapplied with the RESPIMAT® inhaler (2700 μg, twice daily: light greybars, 3712.5 μg in the morning (am): dark grey bars, 3712.5 μg in theevening (pm): black bars) between days 0 and 14 (mean±SEM) (n=7)

B) Temporal variations in lung resistance (R_(L)) associated with theadministration of placebo (white bars) and three different doseschedules of ciclesonide applied with the RESPIMAT® inhaler (2700 μg,twice daily: light grey bars, 3712.5 μg in the morning (am): dark greybars, 3712.5 μg in the evening (pm): black bars) between days 0 and 14(mean±SEM) (n=7)

FIG. 10: Ciclesonide 3^(rd) study: Temporal variations in weightedclinical score associated with the administration of placebo (whitebars) and three different dose schedules of ciclesonide applied with theRESPIMAT® inhaler (2700 μg, twice daily: light grey bars, 3712.5 μg inthe morning (am): dark grey bars, 3712.5 μg in the evening (pm): blackbars) between days 0 and 14 (mean±SEM) (n=7)

FIG. 11: Ciclesonide 3^(rd) study: Temporal variations in serum cortisolassociated with the administration of placebo (white bars) and threedifferent dose schedules of ciclesonide applied with the RESPIMAT®inhaler (2700 μg, twice daily: light grey bars, 3712.5 μg in the morning(am): dark grey bars, 3712.5 μg in the evening (pm): black bars) betweendays 0 and 14 (mean±SEM) (n=7)

FIG. 12: Ciclesonide 4^(th) study: Frequency dependence of meanrespiratory resistance (Rrs) associated with the administration of 2700μg ciclesonide twice daily applied with the RESPIMAT® inhaler betweendays 0 and 14 (mean±SD) (n=1)

FIG. 13: Ciclesonide 4^(th) study: Frequency dependence of meanrespiratory reactance (Xrs) associated with the administration of 2700μg ciclesonide twice daily applied with the RESPIMAT® inhaler betweendays 0 and 14 (mean±SD) (n=1)

FIG. 14: Ciclesonide 4^(th) study: Frequency dependence of meaninspiratory and expiratory respiratory resistance (Rrs) associated withthe administration of 2700 μg ciclesonide twice daily applied with theRESPIMAT® inhaler between days 0 and 14 (mean±SD) (n=1)

FIG. 15: Ciclesonide 4^(th) study: Frequency dependence of meaninspiratory and expiratory respiratory reactance (Xrs) associated withthe administration of 2700 μg ciclesonide twice daily applied with theRESPIMAT® inhaler between days 0 and 14 (mean±SD) (n=1)

DETAILED DESCRIPTION OF THE INVENTION

Both budesonide and ciclesonide are investigated and compared todexamethasone in the same moldy hay challenge model. Both drugs areadministered by the RESPIMAT® inhaler with an adapter for use withhorses (“Equine Inhaler device”) at different dose levels (see examples1 to 3). Both molecules show a comparable efficacy to dexamethasonemeasured in lung function variables (transpulmonary pressure, lungresistance and lung elastance) and clinical score (breathing effortscore and weighted clinical score) (see example 1 and 3). However, theblood levels of cortisol are different between budesonide andciclesonide (see examples 1-3). The cortisol level is comparable betweenthe highest dose of budesonide and dexamethasone after 14 days oftreatment, showing a significant reduction in comparison to the baselinecortisol value (see example 1). In contrast, the cortisol level does notchange significantly after the administration of the highest ciclesonidedose, whereas it is significantly reduced after the administration ofdexamethasone compared to values prior to treatment (see example 3). Inaddition, complete blood count is investigated as well after 14 daystreatment with dexamethasone and ciclesonide. Neutrophilia andlymphopenia are observed after the administration of dexamethasone inboth studies (examples 2 and 3). In contrast, neutrophilia andlymphopenia are not observed after the administration of the differentdoses of ciclesonide.

Before describing the various aspects of the present invention it shallbe noted that as used herein and in the appended claims, the singularforms “a”, “an”, and “the” include plural reference unless the contextclearly dictates otherwise. Thus, for example, reference to “apreparation” includes a plurality of such preparations reference to the“carrier” is a reference to one or more carriers and equivalents thereofknown to those skilled in the art, and so forth. Unless definedotherwise, all technical and scientific terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art towhich this invention belongs. All given ranges and values may vary by 1to 5% unless indicated otherwise or known otherwise by the personskilled in the art, therefore, the term “about” was omitted from thedescription. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, the preferred methods, devices, and materials are nowdescribed. All publications mentioned herein are incorporated herein byreference for the purpose of describing and disclosing the substances,excipients, carriers, and methodologies as reported in the publicationswhich might be used in connection with the invention. Nothing herein isto be construed as an admission that the invention is not entitled toantedate such disclosure by virtue of prior invention. Terms notspecifically defined herein should be given the meanings that would begiven to them by one of skill in the art in light of the disclosure andthe context. As used in the specification, however, unless specified tothe contrary, the following terms have the meaning indicated and thefollowing conventions are adhered to.

The term “ciclesonide”((11β,16α)-16,17-[[(R)Cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione,C₃₂H₄₄O₇, M_(r)=540.7 g/mol) is well known in the art andmeans/describes a glucocorticoid used to treat asthma and allergicrhinitis in humans. It is marketed for application in humans under thebrand name ALVESCO® for asthma and OMNARIS®/OMNAIR® for hay fever in theUS and Canada. Ciclesonide is a prodrug. It is transformed into theactive metabolite C21-C21-desisobutyrylciclesonide (=desciclesonide) viahydrolysis by intracellular esterases in the lung. Ciclesonide is anon-halogenated glucocorticoid, which predominantly exists in its formas R-Enantiomer.

The term “budesonide” is well known in the art and means/describes aglucocorticoid steroid for the treatment of asthma and non-infectiousrhinitis (including hay fever and other allergies), and for treatmentand prevention of nasal polyposis in humans. In addition, it is used forCrohn's disease (inflammatory bowel disease) in humans.

The term “dexamethasone” is well known in the art and means/describes apotent synthetic member of the glucocorticoid class of steroid drugs. Itacts as an antiinflammatory and immunosuppressant. When taken orally, itis 27 times more potent than the naturally occurring hormone cortisoland 7 times more potent than prednisone.

As used herein the term “prodrug” refers to (i) an inactive form of adrug that exerts its effects after metabolic processes within the bodyconverting it to a usable or active form, or (ii) a substance that givesrise to a pharmacologically active metabolite, although not itselfactive (i.e. an inactive precursor).

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative, carrier or precursor of the parent compound or active drugsubstance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). Such prodrugs either havemetabolically cleavable or otherwise convertible groups and are rapidlytransformed in vivo to yield the parent compound, for example, byhydrolysis in blood or by activation via oxidation as in case ofthioether groups. Most common prodrugs include esters and amide analogsof the parent compounds. The prodrug is formulated with the objectivesof improved chemical stability, improved patient acceptance andcompliance, improved bioavailability, prolonged duration of action,improved organ selectivity, improved formulation (e.g., increasedhydrosolubility), and/or decreased side effects (e.g., toxicity). Ingeneral, prodrugs themselves have weak or no biological activity and arestable under ordinary conditions. Prodrugs can usually be readilyprepared from the parent compounds using methods known in the art.

The term “equine” means of or belonging to the family Equidae, whichincludes the horses, asses, and zebras, preferably horses. In addition,the term “equine” encompasses also hybrids of members of the familyEquidae (e.g. mules, hinnies, etc.)

The term “patient” or “subject” embraces mammals such as primatesincludes ing humans. The term “patient” or “subject” as used hereinrelates specifically to horses, especially horses suffering from airwaydisease (particularly pulmonary disease), preferably from recurrentairway obstruction (RAO) also called heaves or equine COPD and/or summerpasture associated obstructive pulmonary disease (SPAOPD) also calledSummer Pasture Associated Recurrent Airway Obstruction (SPARAO) and/orinflammatory airway disease (IAD), most preferably from RAO.

The term “airway disease” in horses means the following: recurrentairway obstruction (RAO) also called heaves or equine COPD, SummerPasture Associated Obstructive Pulmonary disease (SPAOPD), inflammatoryairway disease (IAD), exercise induced pulmonary hemorrhage (EIPH),infectious diseases, chronic interstitial lung disease and upperrespiratory tract functional disorders.

The term “pulmonary disease” means: recurrent airway obstruction (RAO)also called heaves or equine COPD, Summer Pasture Associated ObstructivePulmonary disease (SPAOPD), inflammatory airway disease (IAD), exerciseinduced pulmonary hemorrhage (EIPH), infectious diseases, chronicinterstitial lung disease.

The term “recurrent airway obstruction (RAO)” in horses means thefollowing: a chronic syndrome of mature horses with reversible airwayobstruction in the stable showing periods of labored breathing at restduring exacerbation.

The term “Summer Pasture Associated Obstructive Pulmonary disease(SPAOPD)” in horses means the following: a chronic syndrome, whichshares many clinical and pathological similarities with RAO at rest onthe pasture, suggesting similar pathogenesis, however, it is caused bydifferent antigens.

The term “inflammatory airway disease (IAD)” in horses means thefollowing: a chronic syndrome of horses showing poor performance orcoughing or excess tracheal mucus without showing periods of laboredbreathing at rest.

The term “effective amount” as used herein means an amount sufficient toachieve a reduction of airway disease in a horse when ciclesonide isadministered at a dosage as described herein. The progress of thetherapy (improvement of airway disease, particularly pulmonary disease,preferably recurrent airway obstruction (RAO) and/or Summer PastureAssociated Obstructive Pulmonary disease (SPAOPD) and/or inflammatoryairway disease (IAD), most preferably RAO as described herein) can bemonitored by standard airway/pulmonary diagnosis, for example, byclinical examination, airway fluid cytology, endoscopy, lung functionmeasurement, or blood-gas analysis.

The term “pharmaceutically acceptable derivative thereof” means but isnot limited to pharmaceutically acceptable salts, derivatives,metabolites or pro-drugs of a drug. Derivatives as used herein includebut are not limited to, any hydrate forms, solvates, isomers,enantiomers, racemates, racemic conglomerate and the like of thecompound of choice. Suitable pharmaceutically acceptable salts are wellknown in the art and may be formed with an inorganic or organic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvicacid, malonic acid, succinic acid, glutaric acid, fumaric acid, malicacid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmiticacid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoicacid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonicacid, benzenesulfonic acid and toluenesulfonic acid.

Dosage

The dosage regimen for the treatment of a horse using ciclesonide or acomposition comprising ciclesonide (as an active compound) according tothe present invention will, of course, vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration; the species, age, sex,health, medical condition, and weight of the recipient; the nature andextent of the symptoms; the kind of concurrent treatment; the frequencyof treatment; the route of administration, the renal and hepaticfunction of the patient, and the effect desired.

A physician or veterinarian can determine and prescribe the effectiveamount of the drug required to prevent, counter, or arrest the progressof the disorder.

In the context of the present invention the term “dose” means thedelivered dose “ex inhaler”. Ex inhaler comprises for example apressurized metered dose inhaler (pMDI) or an aqueous/ethanolic dropletinhaler. A specific form of an aqueous/ethanolic droplet inhaler is forexample the RESPIMAT® inhaler or another inhalation device using theRESPIMAT® technology. The concentration of ciclesonide contained in thesolution in the inhalation device ranges preferably from 0.7 to 3.1%m/V.

The systemic dose is determined by measuring the blood levels of theprodrug (ciclesonide) and the activated metabolite(desisobutyryl-ciclesonide) in case systemic exposure is relevant in thehorse. A high systemic dose results in higher side effects for examplereduction of cortisol serum levels.

In addition, radioisotope labeled ciclesonide (e.g. ^(99m)Tc) can beused to examine the distribution of ciclesonide and its metabolites inthe body, especially in the upper and lower airway tract. Based on thecurrently available scientific data, the dose of ciclesonide, when usedfor the indicated effects, will range between 200 and 5000 μg/horse (exinhaler), preferably 400 to 4000 μg/horse (ex inhaler), even morepreferred between 1000 and 3500 μg/horse (ex inhaler), most preferredbetween 1500 and 3100 μg/horse (ex inhaler). Those doses should beadministered once, twice or three times per day, preferably once ortwice daily. In a specific embodiment of the present invention thosedoses should be administered once a day. In another specific embodimentof the present invention those doses should be administered as acombination of twice per day up to 14 days followed by once per day upto 14 days, preferably as a combination of twice per day up to 7 daysfollowed by once per day up to 7 days.

In another specific embodiment of the present invention the dosage (suchas the doses outlined above) can be split into or reduced to anywhere inbetween one dose once in two days up to one dose once in a week. Thetreatment is advisable in clinically apparent cases, both in acute aswell as in chronic settings.

Administration

Suitable forms for “administration” are for example inhalation,parenteral or oral administration.

In the specific administration via the RESPIMAT® inhaler the content ofthe pharmaceutically effective ciclesonide should be in the range from0.1 to 5% m/V, preferably 0.7 to 3.1% m/V or 1.0 to 3.1% m/V of thetotal composition, i.e. in amounts which are sufficient to achieve thedose range specified hereinafter.

When administered by inhalation ciclesonide may be given as an ethanolicsolution or a solution containing a mixture of water and ethanol.Preferably, therefore, pharmaceutical formulations are characterized inthat they comprise ciclesonide according to the preferred aspects above.

It is particularly preferred that ciclesonide is administered viainhalation/ex inhaler, preferably it is administered once or twice aday. Suitable formulations may be obtained, for example, by mixingciclesonide with known excipients, for example water, pharmaceuticallyacceptable organic solvents such as mono- or polyfunctional alcohols(e.g. ethanol or glycerol), or refrigerants such as hydrofluoroalkanes(HFA), specifically HFA 227 and HFA 134a. For a liquid formulation,additional excipients for example hydrochloric acid or citric acid toadjust the [H⁺] concentration may be added.

It is especially preferred that ciclesonide is administered by/via anaqueous/ethanolic droplet inhaler, for example the RESPIMAT® inhaler oranother inhalation device using the RESPIMAT® aerosol-generatingtechnology. Preferably ciclesonide is administered once or twice a day.For this purpose, ciclesonide has to be made available in a liquidsolution which is suitable for the inhaler.

Most preferably the solvent in the liquid formulation (inhalationsolution) comprises a mixture of ≥85% V/V ethanol and ≤15% V/V water,such as 90% V/V ethanol and 10% V/V water.

In a specific embodiment the formulation of ciclesonide is as follows:

TABLE 1 Ingredient Content Ciclesonide 0.7-3.1 g/100 mL Hydrochloricacid ad [H⁺] = 10^(−3.5) to 10⁻⁵ mol/L 90% V/V ethanol/water ad 100 mLwhere the concentration of hydrogen ions [H⁺] can be measured, forexample, by potentiometric titration.

A further aspect of the present invention is the application of theliquid formulation (inhalation solution) using the RESPIMAT® inhaler.This inhaler is disclosed for example in WO 97/12687, which is herebyincorporated therein. This inhaler can advantageously be used to producethe inhalable aerosols according to the invention. The dose of activesubstance delivered ex RESPIMAT® inhaler can be calculated from:

-   -   the concentration of active substance in the liquid formulation        [μg/μL],    -   the “delivered volume”, defined as the volume of liquid expelled        from the RESPIMAT® inhaler per actuation [μL]. The delivered        volume ex RESPIMAT® inhaler has been found to be approximately        11 μL per actuation, according to the following formula:        Dose[μg]=Concentration[μg/μL]·Delivered Volume[μL]

In a further aspect of the present invention the composition isadministered via an (equine) inhaler device. The (equine) inhaler devicepreferably comprises/consists of the RESPIMAT® inhaler, which may bemodified, and other parts to adapt the inhaler to equine use. In apreferred aspect the composition is a partially ethanolic formulationand is administered via an (equine) inhaler device. The dose emitted viathe (equine) inhaler device is slightly lower than the dose ex RESPIMAT®inhaler.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example 1

Budesonide is investigated in a cross-over, blinded moldy hay challengestudy. 8 RAO horses are examined in the study, which is divided into anacclimation and a treatment phase. Placebo for budesonide isadministered a few times per inhalation via the Equine Inhaler device toall horses in the acclimation period. Budesonide and dexamethasone isadministered to the horses in a cross-over design in the treatmentphase. The horses are challenged by exposure to moldy hay throughout theacclimation and treatment periods. Budesonide is administered with thedoses of 450 μg (2 actuations)/900 μg (4 actuations)/1800 (8 actuations)μg/horse (ex-RESPIMAT®) twice daily for 14 days per inhalation via theEquine Inhaler device. Nozzle A and a RESPIMAT® not availablecommercially is used in the study. Nozzle A is the nozzle used with thecommercially available RESPIMAT®. Dexamethasone is administered with adose of 0.066 mg/kg per os, once daily for 14 days. Lung functionvariables (change in transpulmonary pressure, lung resistance and lungelastance), clinical score and blood parameters are examined during thestudy. The data is statistically analyzed using double repeated-measuresANOVA.

All lung function variables are significantly reduced in the highestdose budesonide (1800 μg/horse ex RESPIMAT®) and dexamethasone groupsafter 14 days treatment compared to pretreatment values (p≤0.0001) (seeFIG. 1). There is no significant difference in the lung functionvariables between the highest dose budesonide (1800 μg/horse exRESPIMAT®) and dexamethasone groups after 7 or 14 days treatment. Theclinical score is significantly reduced after 7 and 14 days treatment inall three budesonide and the dexamethasone treatment groups compared topretreatment values (p=0.002 to p<0.0001) (see FIG. 2). There is nosignificant difference in the clinical score between the highest andmiddle dose group of budesonide (900 and 1800 μg/horse ex RESPIMAT®) andthe dexamethasone group after 7 and 14 days treatment. The cortisollevels in serum are significantly reduced in the highest and middle dosebudesonide (900 and 1800 μg/horse ex RESPIMAT®) and dexamethasone groupsafter 14 days treatment compared to pretreatment values (p<0.0001) (seeFIG. 3). There is no significant difference in the cortisol blood levelsbetween the highest and middle dose group of budesonide (900 and 1800μg/horse ex RESPIMAT®) and the dexamethasone group after 14 daystreatment.

Example 2 (1^(st) Ciclesonide Study)

Ciclesonide is investigated in a cross-over, blinded moldy hay challengestudy. 8 RAO horses are examined in the study, which is divided into anacclimation and a treatment phase. Placebo for ciclesonide isadministered twice daily per inhalation via the Equine Inhaler device toall horses for 1 week in the acclimation period. Ciclesonide anddexamethasone are administered to the horses in a cross-over design inthe treatment phase. The horses are challenged by exposure to moldy haythroughout the acclimation and treatment periods. Ciclesonide isadministered with the doses of 450 μg (2 actuations)/900 μg (4actuations)/1800 μg (8 actuations)/horse (ex-RESPIMAT®) twice daily for14 days per inhalation via the Equine Inhaler device. Nozzle A and acommercially available RESPIMAT® is used in the study. Dexamethasone isadministered with a dose of 0.066 mg/kg per os, once daily for 14 days.Lung function variables (change in transpulmonary pressure (ΔPL), lungresistance (RL) and lung elastance (EL)), breathing effort score andblood parameters are examined during the study. The data isstatistically analyzed using double repeated-measures ANOVA.

All lung function variables are significantly reduced in thedexamethasone group after 14 days treatment compared to pretreatmentvalues (p<0.0001) (see FIG. 4). Only the highest dose ciclesonide group(1800 μg/horse ex RESPIMAT®) shows a statistically significant reductionin ΔPL and EL after 14 days treatment compared to pretreatment values(p=0.0005 and p=0.0004). There is no significant difference in ΔPL andEL between the highest dose ciclesonide (1800 μg/horse ex RESPIMAT®) anddexamethasone groups after 14 days treatment. The breathing effort scoreshows no significant changes in any of the treatment groups in any ofthe measured time points.

The serum cortisol levels are significantly reduced in the dexamethasonegroup compared to pretreatment values on days 3, 5, 7, 10, 14 and 17following treatment initiation (p<0.0001) (see FIG. 5). There is nosignificant reduction in the serum cortisol levels in any of theciclesonide treatment groups at any measured time points. The serumcortisol levels in the dexamethasone group are significantly reduced incomparison to any of the ciclesonide treatment groups on days 3, 5, 7,10, 14 and 17 following treatment initiation (p<0.0001). The segmentedneutrophil count is increased and the lymphocytes count is decreasedafter the administration of dexamethasone (see example 4, Table 2).There is no change in the counts of lymphocytes and no or minor increasein the counts of segmented neutrophils after the administration ofciclesonide.

Example 3 (2^(nd) Ciclesonide Study)

Ciclesonide is investigated in a cross-over, blinded moldy hay challengestudy. 8 RAO horses are examined in the study, which is divided into anacclimation and a treatment phase. Placebo for ciclesonide isadministered twice daily per inhalation via the Equine Inhaler device toall horses for 1 week in the acclimation period. Ciclesonide anddexamethasone are administered to the horses in a cross-over design inthe treatment phase. The horses are challenged by exposure to moldy haythroughout the acclimation and treatment periods. Ciclesonide isadministered with the doses of 1687.5 μg (5 actuations, nozzle B)/2700μg (8 actuations, nozzle A)/2700 μg (8 actuations, nozzle B)/horse(ex-RESPIMAT®) twice daily for 14 days per inhalation via the EquineInhaler device. The commercially available RESPIMAT® is used in thestudy. Nozzle A is the nozzle used with the commercially availableRESPIMAT® inhaler. Nozzle B is a different nozzle resulting in a reducedspray time. Dexamethasone is administered with a dose of 0.066 mg/kg peros, once daily for 14 days. Lung function variables (change intranspulmonary pressure (ΔPL), lung resistance (RL) and lung elastance(EL)), weighted clinical score and blood parameters are examined duringthe study. The data are statistically analyzed using doublerepeated-measures ANOVA.

All lung function variables are significantly reduced in all ciclesonideand dexamethasone groups after 14 days treatment compared topretreatment values (p=0.0009 to p<0.0001) (see FIGS. 6A and 6B). Thereis no significant difference in the lung function variables between allciclesonide and dexamethasone groups after 7 or 14 days treatment. Theweighted clinical score is significantly reduced after 14 days treatmentin all three ciclesonide and the dexamethasone treatment groups comparedto pretreatment values (p=0.0001 to p<0.0001) (see FIG. 7). There is nosignificant difference in the weighted clinical score between theciclesonide treatment groups and the dexamethasone group after 14 daystreatment. The serum cortisol levels are significantly reduced in thedexamethasone group on days 3, 5, 7, 10, 14 and 17 following treatmentinitiation (p<0.0001) (see FIG. 8). There is no significant reduction inthe serum cortisol levels in any of the ciclesonide treatment groups atany measured time points. The serum cortisol levels in the dexamethasonegroup are significantly reduced in comparison to any of the ciclesonidetreatment groups on days 3, 5, 7, 10, 14 and 17 following treatmentinitiation (p<0.0001). The segmented neutrophil count is increased andthe lymphocytes count is decreased after the administration ofdexamethasone (see example 4, Table 2). There is no change in the countsof lymphocytes and no or minor increase in the counts of segmentedneutrophils after the administration of ciclesonide.

Example 4

The segmented neutrophil counts and the lymphocyte counts are determinedin the studies above: ciclesonide treatment versus dexamethasonetreatment. For experimental setup and description of the conduction ofthe studies see examples 2 and 3.

TABLE 2 Concentration of segmented neutrophils and lymphocytes on day(D): D 0, D 14 and D 21 in the treatment groups of dexamethasone anddifferent doses of ciclesonide (n = 8) (mean +/− SEM) Segmentedneutrophils Lymphocytes (×10⁹/L) (×10⁹/L) D 0 D 14 D 21 D 0 D 14 D 21Dexamethasone 4.77 6.16 4.27 2.10 1.71 1.76 (1st ciclesonide (1.34)(1.28) (1.23) (0.70) (0.52) (0.43) study) Dexamethsaone 4.82 6.23 4.822.14 1.73 1.73 (2nd cicleso- (1.51) (1.45) (1.04) (0.62) (0.62) (0.34)nide study) 450 μg cicleso- 4.66 4.98 5.48 1.96 1.97 2.17 nide (1.32)(1.75) (1.51) (0.36) (0.36) (0.50) 900 μg cicleso- 5.24 4.43 4.91 1.852.03 1.94 nide (1.10) (1.06) (2.48) (0.28) (0.49) (0.34) 1800 μg 4.605.41 4.93 1.95 1.96 2.06 ciclesonide (1.33) (1.68) (1.10) (0.48) (0.64)(0.57) 1687.5 μg 4.51 5.22 4.55 1.93 1.94 2.04 ciclesonide (1.61) (2.54)(1.80) (0.48) (0.33) (0.41) 2700 μg 4.91 4.85 4.41 2.04 2.14 2.01ciclesonide A (1.45) (1.10) (1.75) (0.57) (0.41) (0.43) 2700 μg 4.234.75 4.84 1.80 1.74 2.01 ciclesonide B (1.17) (2.02) (1.55) (0.45)(0.36) (0.57) (second ciclesonide study)

Neutrophilia and lymphopenia is observed after the state of the arttreatment with dexamethasone (see Table 2). In contrast, no alterationis observed in the immune system of horses measured by neutrophilia andlymphopenia after treatment for two weeks with different dose levels ofciclesonide (see Table 2).

Example 5

The concentration of ciclesonide and C21-C21-desisobutyrylciclesonide isdetermined in plasma samples in the above mentioned 2^(nd) ciclesonidestudy: ciclesonide treatment versus dexamethasone treatment. Forexperimental setup and description of the conduction of the study seeexample 3. The plasma level of ciclesonide andC21-C21-desisobutyryl-ciclesonide are determined by high performanceliquid chromatography coupled to tandem mass spectrometry. Plasmasamples are collected prior to and 10, 30 min, 1, 2 and 4 h followingciclesonide administration on day 1 and 11 of the treatment phase withciclesonide.

TABLE 3 Concentration of ciclesonide and C21-C21-desisobutyrylciclesonide in equine plasma after administration ofciclesonide (n = 8) (mean) Dose of ciclesonide (μg)/Nozzle 0 min 10 min30 min 1 h 2 h 4 h Ciclesonide concentration on day 1 (nmol/L) 1687.5 B<0.500 0.87 <0.500 <0.500 <0.500 <0.500 2700 A <0.500 1.19 0.51 <0.500<0.500 <0.500 2700 B <0.500 1.16 0.72 <0.500 <0.500 <0.500 Ciclesonideconcentration on day 11 (nmol/L) 1687.5 B <0.500 0.97 <0.500 <0.500<0.500 <0.500 2700 A <0.500 1.02 0.63 <0.500 <0.500 <0.500 2700 B <0.5001.38 0.63 <0.500 <0.500 <0.500 C21 -C21-desisobutyrylciclesonideconcentration on day 1 (nmol/L) 1687.5 B <0.250 0 0.38 0.34 0.38 <0.2502700 A <0.250 0.35 0.45 0.47 0.3 <0.250 2700 B <0.250 0.28 0.59 0.480.34 <0.250 C21 -C21-desisobutyrylciclesonide concentration on day 11(nmol/L) 1687.5 B <0.250 0.3 0.37 0.39 0.3 <0.250 2700 A <0.250 0.4 0.570.44 0.34 <0.250 2700 B <0.250 0.36 0.51 0.43 0.35 <0.250

The concentration of ciclesonide is below the lower limit ofquantification (0.5 nmol/L) in the plasma samples taken 1 h after drugadministration. The concentration of C21-C21-desisobutyrylciclesonide isbelow the lower limit of quantification (0.25 nmol/L) in the plasmasamples taken at 4 h after the administration of ciclesonide.

Example 6 (3^(rd) Ciclesonide Study)

Ciclesonide is investigated in a cross-over, blinded moldy hay challengestudy examining 7 RAO horses. Ciclesonide and placebo for ciclesonideare administered to the horses in a cross-over design. The horses arechallenged by exposure to moldy hay throughout the whole study.Ciclesonide is administered with the doses of 2700 μg, twice daily (8actuations twice daily)/3712.5 μg, once daily in the morning (11actuations once daily in the morning)/3712.5 μg, once daily in theevening (11 actuations once daily in the evening)/horse (ex-RESPIMAT®)for 14 days per inhalation via the Equine Inhaler device. Placebo forciclesonide is administered with a dose of 0.0 μg ciclesonide/horse(ex-RESPIMAT®) twice daily for 14 days per inhalation via the EquineInhaler device. The commercially available RESPIMAT® with nozzle B isused in the study (please see example 3 for description of nozzle B).Lung function variables (change in transpulmonary pressure (ΔPL), lungresistance (RL) and lung elastance (EL)), weighted clinical score andblood parameters are examined during the study. The data arestatistically analyzed using double repeated-measures ANOVA.

The lung function variables are significantly reduced in the ciclesonidetreatment groups after 14 days treatment compared to the pretreatmentvalues and compared to the placebo group as well. ΔPL and RL aresignificantly reduced in the 2700 μg (twice daily) ciclesonide group andRL is significantly reduced in the 3712.5 μg (once daily in the evening)ciclesonide group after 14 days treatment compared to pretreatmentvalues (2700 μg: p<0.0001 for ΔPL and RL, 3712.5 μg: p=0.0001) (seeFIGS. 9A and 9B). The reduction of ΔPL and RL is statisticallysignificant in the 2700 μg ciclesonide group after 7 days treatmentcompared to pretreatment values (p<0.0001). There is a significantdifference in the lung function variables between all ciclesonide andplacebo groups after 14 days treatment (ΔPL: 2700 μg and 3712.5 μg inthe evening: p<0.0001, 3712.5 μg in the morning: p=0.0005, RL: 2700 μgand 3712.5 μg in the evening: p<0.0001, 3712.5 μg in the morning:p=0.0003). The change in ΔPL is significantly reduced in the 2700 μgtwice daily (p<0.0001) and the 3712.5 μg once daily in the evening(p=0.001) ciclesonide groups after 7 days treatment compared topretreatment values The reduction of RL is statistically significantafter 7 days treatment compared to the pretreatment values in the 2700μg ciclesonide treatment group (p=0.0002). There is no significantreduction in the lung function variables of the placebo group after 14days treatment compared to the pretreatment values.

The weighted clinical score is significantly reduced in the 2700 μg(twice daily) ciclesonide group after 7 and 14 days treatment comparedto pretreatment values (7 days: p=0.0001, 14 days: p=0.0003) (see FIG.10). There is significant difference in the weighted clinical scorebetween the ciclesonide treatment groups and the placebo group after 14days treatment (2700 μg and 3712.5 μg in the evening: p=0.0002, 3712.5μg in the morning: p=0.0006). There is no significant reduction in theserum cortisol levels in any of the ciclesonide treatment groups and inthe placebo group at any measured time points (see FIG. 11). There is nochange in the counts of lymphocytes and no or minor increase in thecounts of segmented neutrophils after the administration of ciclesonideand placebo (see table 4).

TABLE 4 Concentration of segmented neutrophils and lymphocytes on day(D): D 0, D 14 and D 21 in the treatment groups of placebo and differentdoses of ciclesonide (n = 7) (mean +/− SEM) Segmented neutrophilsLymphocytes (×10⁹/L) (×10⁹/L) D 0 D 14 D 21 D 0 D 14 D 21 Placebo 4.124.27 3.86 2.33 2.29 2.50 (0.98) (1.28) (1.10) (0.48) (0.25) (0.33) 2700μg 3.97 4.57 3.47 2.55 2.54 2.49 ciclesonide (0.79) (1.40) (0.85) (0.58)(0.57) (0.55) (3rd cicleso- nide study) 3712.5 μg 4.37 4.45 3.75 2.212.48 2.66 (morning) (0.96) (1.02) (1.15) (0.30) (0.48) (0.48) 3712.5 μg3.73 4.37 3.41 2.55 2.43 2.48 ciclesonide (1.23) (1.21) (0.70) (0.37)(0.34) (0.35) (evening)

Example 7 (4^(th) Ciclesonide Study)

Ciclesonide is investigated in a baseline controlled, blinded studyexamining one (1) IAD horse. Ciclesonide is administered with the doseof 2700 μg, twice daily (8 actuations twice daily)/horse (ex-RESPIMAT®)for 14 days per inhalation via the Equine Inhaler device. Thecommercially available RESPIMAT® with nozzle B is used in the study(please see example 3 for description of nozzle B). Lung functionvariables using the impulse oscillometry system (respiratory resistance(Rrs) and reactance (Xrs) are examined during the study.

The mean respiratory resistance of three measurements is decreased afterthe administration of 2700 μg ciclesonide for 14 days to one IAD horseat frequencies between 0.2 to 20 Hz compared to the pretreatment values(see FIG. 12). The mean respiratory reactance of three measurements isdecreased after the administration of 2700 μg ciclesonide for 14 days toone IAD horse at frequencies between 5 to 10 Hz compared to thepretreatment values (see FIG. 13). In contrast to the pretreatmentvalues (DO) the mean respiratory resistance of three measurements ininspiration and expiration are not different after the administration of2700 μg ciclesonide for 14 days at frequencies between 0.2 to 2 Hz (seeFIG. 14). In contrast to the pretreatment values (DO) the meanrespiratory reactance of three measurements in inspiration andexpiration are not different after the administration of 2700 μgciclesonide for 14 days at frequencies between 0.2 to 2 Hz (see FIG.15).

REFERENCES

-   Kutasi O., Balogh N., Lajos Z., Nagy K., Szenci O.: Diagnostic    approaches for the assessment of equine chronic pulmonary    disorders. J. Eq. Vet. Sci. (2011) 31: 400-410-   Coutil L. L, Hoffman A. M., Hodgson J., Buechner-Maxwell V., Viel    L., Wood J. L. N. and Lavoie J.-P.: Inflammatory airway disease of    horses. J. Vet. Intern. Med. (2007) 21: 356-361-   Dauvillier J., Felippe M. J. B., Lunn D. P., Lavoie-Lamoureux A.,    Leclere M., Beauchamp G., Lavoie J.-P.: Effect of long-term    fluticasone treatment on immune function in horses with heaves. J.    Vet. Intern. Med. (2011) 25: 549-557-   Grahnén A., Jansson B., Brundin R. M., Ling-Andersson A., Lönnebo    A., Johansson M. and Eckernas S.-A.: A dose-response study comparing    supression of plasma cortisol influenced by fluticasone propionate    from Diskhaler and budesonide from Turbohaler. Eur. J. Clin.    Pharm. (1997) 52: 261-267-   Robinson N. E., Berney C., Behan A and Derksen F. J.: Fluticasone    propionate aerosol is more effective for prevention than treatment    of recurrent airway obstruction. J. Vet. Intern. Med. (2009) 23 (6):    1247-1253

The invention claimed is:
 1. A method of treating an airway disease inequines comprising administering by inhalation to an equine having anairway disease an effective amount of ciclesonide or a pharmaceuticallyacceptable salt thereof or a composition comprising ciclesonide or apharmaceutically acceptable salt thereof during a treatment periodcomprising a first portion and optionally a second portion, wherein theeffective amount administered during the first portion of the treatmentperiod comprises a daily dose of at least 5000 μg ex inhaler forconsecutive days and the effective amount administered during theoptional second portion of the treatment period comprises a daily doseof at least 100 μs to 5000 μg ex inhaler.
 2. The method according toclaim 1, wherein the airway disease is a pulmonary disease.
 3. Themethod according to claim 1, wherein the airway disease is selected fromthe group consisting of: recurrent airway obstruction (RAO), summerpasture associated obstructive pulmonary disease (SPAOPD), andinflammatory airway disease (IAD).
 4. The method according to claim 3,wherein the airway disease is RAO.
 5. A method according to claim 1,wherein said ciclesonide or said pharmaceutically acceptable saltthereof or said composition comprising ciclesonide or saidpharmaceutically acceptable salt thereof is in a liquid formulation. 6.A method according to claim 5, wherein said liquid formulation comprisesone or more of the solvents water, ethanol, hydrofluoroalkanes,hydrofluoroolefin or excipients.
 7. A method according to claim 6,wherein said hydrofluoroalkanes are HFA 227, HFA 134a, and combinationsthereof.
 8. A method according to claim 6, wherein saidhydrofluoroolefin is HFO1234ze.
 9. A method according to claim 5,wherein the solvent in said liquid formulation is partially aqueous andpartially ethanol.
 10. A method according to claim 9, wherein thesolvent in said liquid formulation comprises of a mixture of ≥85% V/Vethanol and ≤15% V/V water.
 11. A method according to claim 9, whereinthe solvent in said liquid formulation comprises 10% V/V water and 90%V/V ethanol.
 12. A method according to claim 5, wherein said ciclesonideor said pharmaceutically acceptable salt thereof or said compositioncomprising ciclesonide or said pharmaceutically acceptable salt thereofis administered via an inhaler device.
 13. The method according to claim12, whereby said inhaler device comprises: a. a pressurized metered doseinhaler or a aqueous/ethanolic droplet inhaler; and b. an adapter forequine use.
 14. A method according to claim 5, wherein said ciclesonideor said pharmaceutically acceptable salt thereof or said compositioncomprising ciclesonide or said pharmaceutically acceptable salt thereofis a partially ethanolic formulation and is administered via an inhalerdevice.
 15. A method according to claim 14, wherein the method includesboth the first and second portions, and the effective amountadministered during the second portion of the treatment period comprisesa daily dose of at least 900 μg ex inhaler, at least 1800 μg ex inhaler,or at least 2700 μg ex inhaler.
 16. The method according to claim 1,wherein the method includes both the first and second portions, andwherein the effective amount administered during the treatment periodcomprises a first dose administered twice daily for a period of 5-7 daysduring the first portion and a second dose administered once daily for aperiod of 5-7 days during the second portion.
 17. The method accordingto claim 16, wherein the first dose is 2700 μg ex inhaler administeredtwice daily and the second dose is 3712.5 μg ex inhaler administeredonce daily.
 18. The method according to claim 1, wherein the compositioncomprises a solution comprising 0.7-3.1 g ciclesonide/100 mL.
 19. Amethod of treating an airway disease in equines comprising administeringby inhalation to an equine an effective amount of ciclesonide or apharmaceutically acceptable salt thereof or a composition comprisingciclesonide or a pharmaceutically acceptable salt thereof, wherein theeffective amount results in no significant reduction in a cortisol levelwithin the blood of the equine after treatment for a period of twoweeks.
 20. The method according to claim 1, wherein the effective amountadministered during a treatment period of two weeks results in adecrease in a cortisol level within the blood of the equine of nogreater than 19% after the treatment period of two weeks.